DESCRIPTION: This revised application seeks to renew an ongoing project that proposes to define the metabolic basis for the relative insulin deficiency loci of type 2 diabetes by exploring its genetic basis. The focus of this application is on Ashkenazi Jews, a genetically distinct Caucasian Population. The hypothesis to be tested is that a few major genes are responsible for type 2 diabetes. A total of 289 families with two or more affected individuals were collected in Israel. An initial genome scan with STR markers at 9.5 cM intervals was completed. Six chromosomal regions with nominal evidence for linkage (multipoint LOD greater than 1.0) were identified. Three specific aims are proposed. First, they will complete linkage analysis in families by genotyping additional individuals with more dense markers across the 6 regions. In addition, nondiabetic controls (n=150) will be genotyped for association studies. Second, based on linkage results for chromosome 20q in Ashkenazi Jews and in Finns of the FUSION study, collaborative association studies with MSP and SNP markers will be conducted to narrow the region. In addition, based on linkage and association results, other chromosomal regions may be fine mapped by LD analysis in unrelated individuals. This will require construction of physical maps on the regions, identification of as many as 300 SNPs at 30 kb intervals. Diabetes and controls and discordant sibs will be genotyped. Because of its unique genetic composition, Ashkenazi Jews may represent the best cohort of patients in which to conduct this type of analysis for a complex disease. Third, from any region narrowed to less than 1 Mb by LD, positional cloning will be undertaken. Candidate genes will be identified within the region by completion of genomic sequencing, followed by mutational analysis. Once the gene is identified in this Caucasian group, the gene can then be assessed for its contribution to diabetes in other racial groups. In the preceding 3 years the group has moved closer to their original stated goal of identification of type 2 diabetes genes. Defining the nature of these gene defects will enhance efforts toward achieving the long-range goal of determining the metabolic basis of type 2 diabetes. Knowledge of the etiology through identifying its genetic basis will serve to facilitate early diagnosis, treatment and prevention. This grant seeks to define the etiology of the metabolic defects in T2DM by clarifying its genetic basis.